Document 8R8pZB7kEB9nZE8kBa5r6BRxk

Sr-cr'ents f!T- TC CAL!!-' THE TOXICOLOGY OF PCB'S An Overview with Emphaaia on Human Health Effects and Occupational Exposures Hazard Evaluation Syitam and Information Service Stata of California Oapartmant of Health Sarvicaa/Dapartmant of Industrial Relations January, 1981 (Updated February 1982) V MOMS 221431 THE TOXICOLOGY OP PCBe An Overview with Emphasis on Human Health Effects and Occupational Exposures Prepared by Gideon Letz, M.D., M.P.H. Hazard Evaluation System and Information Service State of California Department of Health Services/Department of Industrial Relations 2151 Berkeley Way Berkeley, California 94700 (415) 540-2115 MOHS 221432 THE TOXICOLOGY OF PCBs Table of Contents I. INTRODUCTION...................................................................................................4 D, GENERAL BACKGROUNDINFORMATION.....................................................6 III. PHARMACOKINETICS............................................................................... ....... Absorption.......................................... ............................................................ g Distribution, Accumulation (Mammeis). , ,.......................................... j Transplacental Exposure, Secretion in Milk.................................................. Metabolism . ............................................................................................ .... IV. ANIMAL TOXICOLOGY............................................................................... .... Acute.................................................................................................................. Subacute, Chronic............................................................................................... 14 Reproductive Effects................................................................................ .... Other - Immunesupprelive, Endocrine............................................................IS V. CARCINOGENICITY/MUTAGENICITY...........................................................20 Carcinogenicity.....................................................................................................20 Test Results.............................................-................................................. 20 Mutagenicity..................................................................................................... 23 VI. BIOCHEMICAL EFFECTS...................................................................................25 Enzyme Induction...............................................................................................25 Porphyria...........................................................................................................26 VII. HUMAN TOXICOLOGY AND EPIDEMIOLOGY........................................ 2S Dermatologic Effects .........................................................................................28 Systemic Symptoms.........................................................................................29 Liver Damage.....................................................................................................29 YushO.................................................................................................................29 Netrotoxidty..................................................................................................... 31 Cancer................................................................................................................. 32 Ongoing Occupational Studies .... 33 VIE. MEDICAL SURVEILLANCEAND BIOLOGIC MONITORING ... 36 IX. SUMMARY AND CONCLUSIONS..................................................................38 - 2- HONS 221433 Table ol Contents REFERENCES.................................................................................................................. 39 Table I. Dose-Response for Animal Toxicology........................................... .... Table 0. Occupational Exposure to PCBs....................................................... ..... Table HI. Percent Distribution of Symptoms of Yusho Reported by 189 Patients Examined Before October 3, 1968................................... 50 Figure 1.............................................................................................................................. Figure n............................................................................................................................. Figure 111. ..................................................................................................................... 32 Figure IV. ..... 53 -3- MOMS 221434 1. INTRODUCTION As * consequence of the Environmental Protection Agency (EPA) ban on further manufacture of polychlorinated biphenyls (PCBs) in 1977, occupational exposures to these compounds have been drastically reduced. However, significant exposures may remain for particular occupational groups. Utility workers, for example, may experience sporadic but potentially massive exposures when cleaning up spills, or when servicing and dismantling transformers and capacitors that still contain PCB fluid. Electricians, appliance service workers and firefighters also may have continued occupational exposire. The National Institute of Occupational Safety and Health (NIOSH) estimates that 12,000 workers have potential exposure as a result of current uses of PCBs (NIOSH, 1977). Despite the vast scientific literature on the toxicology of PCBs, the human health effects likely to result from such exposure remain UJdeflned. The Hazard Evaluation System and Information Service (HESIS) has reviewed the literature on PCB toxicology in response to inquiries about worker health. Requests for Information have oome from unions and workers who handle PCB fluids in cleanup of spills, in maintenance work, and in transportation, storage and disposal of used equipment. Toxicology information has also been revested by medical professionals evaluating the clinical significance of PCB exposures, and public health officials who are attempting to set standards for occupational and environmental exposures. Our primary goal has been to review the data relevant to the human health effects of FCBs especially those resulting from occupational exposures. Since the published epidemiologic evidence is limited we have utilized animal toxicology studies where appropriate in anticipating potential biologic effects in humans. We have not attempted to summarize the extensive literature on PCB toxicology, but the reader Is referred -S MOMS 221435 to a number of recent review* (DHEW, 197Sj IARC, 197S; Fifhbein, 1974; Kimbrough, 19791 EPA, 1977j Nelon, I972j NIOSH, 1977). -5- HOMS 221436 II. GENERAL BACKGROUND INFORMATION In ail animal species that have been studied PCBs have a very low acute toxicity. They are readily absorbed across biological membranes, poorly metabolized and only very slowly eliminated. Because PCBs persist in the environment and accumulate in living tissue, they are concentrated ("biomagnified") in the food chain in a similar manner to other organochlorine compounds like DDT. Concern about exposure to PCBs has, therefore, focused on their resistance to biodegradation with the consequent potential for long-term or delayed health effects. A number of published reports have established "background" levels of PCBs in the blood and tissues of human populations with no previous history of exposure. Surveys in various geographical areas have found detectable residues in blood, fat and mothers' milk. Measurable levels of PCBs are typically found in greater than 30% of subjects tested with maximum blood levels generally less than 20 ppb (Finklea, 1972). The levels reported from adipose tissue are typically somewhat higher, in the range of 1-2 ppm (Kutz, 1973). Residues of PCBs in human milk have ranged from (*0-100 ppb in whole milk (New York State Health Council, 1977X Two facts complicate the documentation of the human and animal toxioology of PCBs: 1. Commercial products are rarely single agents, but rather are complex mixtures of chlorinated biphenyls with different numbers and arrangements of attached chlorine atoms (see Figure 1). The metabolism and toxioology of PCBs seem to vary with the percent of chlorination and with the isomeric structure of the PCB molecule. 2. All commercial products are potentially contaminated with chlori nated naphthalenes and polychlorinated dibenzofurans (PCDFs). The degree of this contamination vanes with different commercial mixtures (see Figure III). - 6- HONS 221437 Contamination by dibenzofurans (PCDFs) is of particular concern because of the structural similarity of these compounds to the highly toxic dibenzodioxins (see Figure ID. The pattern of observed effects in animals exposed to PCDFs closely resembles that seen following exposure to 2,3,7,S tetrachlorodibenzodioxin (TCDD), In comparative animal studies the toxicity of PCDFs is much greater than the PCBs, particularly in the thymus, skin (acne), liver and hematopoetlc system (Oishi et al.. 197Si Moore et al., 1979X In addition, PCDFs are 1000 times more potent than PCBs as enzyme inducers (see Section VI). Uncertainties in the analytic methods used for detection of PCBs must be considered when reviewing the published data on PCB toxicology! Monitoring PCBs In environmental or biological samples by gas-Uquid chromatography/mass spectrometry (GC/M5) is made difficult by the presence of other chlorinated hydrocarbons (e.g., pesticides) which are commonly present at similar concentrations (Stalling et al>, 1979). Because of the difficulties In the interpretation of GC/M5 spectra and other methodologic problems includlr^ extraction and cleanup, the PCB levels reported from different laboratories may show considerable variation. -7- MOMS 221438 Dl. PHARMACOKINETICS Absorption There is relatively little information on the rate or degree of absorption of PCBs by any route for any species of animal Since similar systemic toxicity has been observed in rodents after dermal oral and inhalational adminstration of comparable doses, it is likely that PCBs are easily absorbed by all routes. The few quantitative measurements of relative absorption rates indicate that most, if not all, PCBs which contain six or fewer chlorine atoms are efficiently absorbed from the gastrointestinal (Cl) tract (Albro and Flshbeln, I972( Van Miller et al. I973j Matthews and Anderson, 1973). Distribution, Accumulation (Mammals) As with other heavily chlorinated chemicals the major storage tissue for PCBs is body fat. The concentration in adipose tissue is 10-1000 times that found in other tissues, both following single oral doses (Grant et al, 1971) and after chronic administration. (Curley et al, 1971) The lowest concentrations are found in whole blood and plasma where levels are usually several fold lower than in other tissues examined. This preferential distribution of PCBs into fat has been well documented after intravenous (l.v.) dosing in the rat (Lutz et al, 1977). Results are consistent with the high distribution coefficient of PCBs in fat and low perfusion of adipose tissue compared to skin, liver, muscle and blood (Anderson et al., 19771 Two Important pharmacokinetic questions cannot now be resolved on the basis of available data! 1, Does the concentration of PCBs reach steady state with constant exposire? - S- MOWS 221439 2. Will mobilization of adipose tissue after starvation or illness lead to a transient increase in PCB concentrations in blood and other tissues ? Like most heavily chlorinated hydrocarbons the half-life of PCBs in animal tissue is quite long. In a chronic feeding study with Arodor 1254 at 100 ppm in the diet of rats, a steady build-up of PCBs occurred In all tissues analyzed without a plateau level even after 240 days of treatment. By comparison, In a similar rat dietary study using DDT, plateaus in fat were attained after 90-140 days (Curley et aL. 1971). In dairy cows a steady state was reached in 40-60 days (Fries, 1972), probably due to mobilization Into fat micelles and secretion Into milk. Thus, PCBs are unlikely to reach steady state levels in nonlactating animals} and fat mobilization or lactation may be expected to result in release of stored PCBs. Transplacental Exposure, Secretion in Milk Transplacental exposure of PCBs has been documented in mammals. Term fetuses taken from rats exposed to 10 mg/kg/day during days 7-15 gestation contained 0.63 ppm PCB, or about 1/60 the maternal dose. When the dose to the mother was increased five fold, the concentration in the fetuses increased two fold (Curley et al., 1973). The hyperpigmented babies observed in the Yusho incident (see Section VII) represent additional circumstantial evidence of transplacental passage of PCBs, although it is unclear whether these effects were related to PCB or to the PCDF contamination. Secretion of PCBs into milk has also been observed. In mice, little passage of PCBs occurred across the placenta once PCBs had been sequestered into maternal adipose tissue, but they were readily transferred to suckling offspring through the milk (Vodicnik and Lech, 19S0). These observations suggest that secretion of PCBs into milk may be quantitatively much more important as a source of exposure in newborns than is -9- MOMS 221640 transplacental passage. This has recently been documented in a prospective study of Japanese mothers and their infants (Hirokadzu and Ota, 19S0). Metabolism PCBs are metabolized primarily by hydroxylation and conjugation with glucuronic acid. The primary site of biotransformation is assumed to be the liver, although no data is available currently on the possible role of peripheral metabolism, e.g,, skin. Many experimental feeding studies in both mammals and birds have shown an inverse relationship between percent ^icrination and rates of metabolism. Less chlorinated PCBs are more readily metabolized than are more chlorinated ones, the rate of metabolism and excretion decreasihg sharply as the number of chlorine atoms increases above five (EPA, 1977). The metabolism of the higher chlorinated biphenyls is also dependent on the position of chlorine atom substitution. The presence of two adjacent, unsubstituted carbon atoms is needed for the rapid enzymatic hydroxylation reaction (Jensen and Swdstrom, 1974). Since the more highly chlorinated biphenyls have a very much slower metabolic rate and longer half-life, they are more generally found as residues in human and animal tissues. This relationship alters with PCBs above 54% chlorination, presumably as a result of lower absorption from the gastrointestinal tract. Arene oxide intermediates have been described in a major pathway of the metabolic transformation of PCBs by hepatic mixed function oxidases (Safe et aU 1973; Gardner et !.. 1973). These intermediates are of particular concern since they are capable of direct interaction with DNA and may be the active form of carcinogenic polyacyclic hydrocarbons (Jerina and Daly, 1974). The PCB molecules which are more readily metabolized and excreted also are more likely to form these arene oxides. It does - 10 HONS 221441 not necessarily follow, however, that those compounds which persist in tissue and are more likely to be measured in population sampling, are less important in terms of their carcinogenic potential. From the limited data available, It appears that significant differences exist between nonhuman primates and rodents in the metabolism and pharmacokinetics of PCBs. The marked variation observed in PCB toxicity between rodents and primates .nay be explained by such differences. Primates appear to be more susceptible to the toxic effects of PCBs than are rats or mice (see Section IV and Figure IV). When single doses of radiolabeled PCB were administered by gastric intubation to infant monkeys, the metabolites measured in urine, tissue (liver) and serum included hydroxylation products derived from arene oxide intermediates while In the rat, direct hydroxylation is the rule (Hsu et aL, 1975). There Is virtually no pharmacokinetic data in humans. A few generalizations can be made, however, based on studies reporting PCB blood levels: the higher the exposure levels, the higher blood concentration of PCBs (Hara et at, 1975; Inoue et aL. 1975; Karppanen and Lolho, 1973; Baker et aL. 1980); and the higher the environmental concentration and/or the longer the period of exposure, the longer the blood levels of PCBs remain elevated (Hara et al., 1975; Baker et ai., 1980). However, there are a few reports whidi are Inconsistent with this latter trend (Bumgarrer et al., 1975; Haseaawa et aU 1972; Kltamura et al., 1973). PCB levels have also been correlated with race and geographic residence (NtOSH, 1977) and with age and dietary intake of fish (Kimbrough, 1980). - 11 - HONS 221442 Comment! Ca-tain generalizations can be made from the limited pharmacokinetic data that is available: 1. Absorption occurs by all routes (skin, Gt, inhalation). 2. Distribution is primarily into fat. 3. Metabolism and excretion are dependent on specific molecular structure, varying inversely with percent chlorination. 4. Excretion is in general ^iite slow so that bioaccumulation occurs even at low exposure levels. 5. Transplacental transfer occurs but may be quantitatively less significant than secretion into milk. 6. Arena oxide metabolites are found in the metabolic transformation ol PCBs. These compounds are highly reactive and may represent the active carcinogens (see Section V). 7. The relationship between percent chlorination and potency as carcinogen has not been established. g. There are essentially no pharmacokinetic data in humans; it is not known, for example, if intermittent high doses are more or less hazardous than low level chronic exposures to the same total dose. 12 - MOMS 221*43 IV. ANIMAL TOXICOLOGY Acute Toxicity When given as a single dose, the acute oral LDj0 of PCBs In rats, rabbits and mice ranges from I-10 g/kg of body weight. According to the American Industrial Hygiene Association classification system far acute toxicity, PCBs are classified as "slightly toxic" (0.5-5 g/l^X or "practically nontoxic" (5-15 g/kg). There Is some evidence that i young animals are more sensitive than adults, and that females are more susceptible than males to the acute effects of PCBs (Kimbrough et aL. 1971). In rodents, the acute oral toxicity appears to decrease with increasing chlorine content of the administered PCBs. This may be secondary to decreased absorption of the higher chlorinated compounds or to the differences in metabolic transformation previously discussed. Although few clinical signs of toxicity have been reported in experimental animals, pathologic findings are extensively documented. Central Nervous System (CNS) depression (decreased pain response and diminished ei^loratory behavior), anorexia and oliguria followed by ataxia, coma and death have been observed in rats following acute administration of large doses of PCBs (Brackner et aL. 1973). Consistent pathologic findings associated with death in'rats, rabbits and guinea pigs include liver damage with fatty infiltration, centrolobular atrophy, and in some cases necrosis. Pathologic changes in other organs in these species are not often described, except for chioracnelike lesions whldi occur at the site of skin or intradermal application. - 13 MONS 221444 Comment! The low order of acute toxicity in experimental animals is consistent with the lack of acute effects observed in workers exposed to PCBs. Reporter symptoms after occupational exposures include mild Irritation of the skin and eyes at levels above 0.1 mg/m with unbearable irritation occurring above 10 mg/mJ (ACGIH, 1976). Systemic symptoms of nausea and headache have been reported but may be secondary to the solvents (such as trichlorobenzene) in the PCB mixtures. Subacute and Chronic Toxicity In contrast to the low order of acute toxicity, effects from chronic exposures to relatively low doses of PCBs have been consistently observed and are of far greater concern. These subacute effects show appreciable variation among species, but liver damage is again the prominent finding. The major changes in rats fed Arocior 124$, 1254, and 1262 at 100 ppm in their diet for six weeks included liver hypertrophy, marked fatty infiltration and degeneration of parenchymal cells. As in acute toxicity studies, PCB mixtures with lower chlorine content were more toxic (Allen and Abrahamson, 1973). In S-12 month feeding studies increased serum lipids and focal areas of liver damage were observed (Alien ct ah, 1976| Kimbrough at ai.. 1972). Nonhuman primates are more sensitive than rodents to the toxic effects of PCBs (see Table 1 and Figure IV). Adult female monkeys exposed to dietary levels of 2.3 ppm for 12 months (*0.08 mg/kg/day) developed facial edema, alopecia, acne, gastritis with uioeratlon, anemia, hypoproteinemia and bone marrow hypoplasia. At 100 ppm (*10 mg/kg/day) there was considerably more evidence of tissue damage than in rats, !h - MOWS 221445 Including marked hepatic hypertrophy with ultrastructural abnormalities (Allen. 1973). Based on extrapolation from the Yusho data, PCBs may cause symptoms to burners at levels (0.2 mg/lq/day) which are comparable to the lowest doses which produce effects in nonhumwt primates (see Table IX Most of the animat data are derived from feeding or oral Intubation studies. There are relatively few reports of dermal or inhalation experiments. Inhalation studies again revealed liver damage to be the prominent finding In rodents. For summary of inhalation data see the NIOSH criteria document, page 123 (NIOSH, 1977). Dermal toxicity studies In rabbits have produced skin lesions at the site of application as well as systemic effects including liver and kittoey damage, thymic atrophy, lymphopenia and Increased fecal porphyrins (Vos and Beams, 1971). Comments Liver <tamage, documented histologically, is the most consistent finding among the many laboratory animals species tested. Effects of low level chronic exposure does show appreciable variation among species, but liver damage has been observed in ail species and Is usually the most sensitive indication of PCB exposure. The fact that liver dysfunction has been inconsistently observed In humans may be an artifact of the relative insensitivity of the standard liver function tests (SCOT, SGPT) as compared to biopsy and histologic analysis (see Sec. VO, p. 25X Reproductive Effects Adverse reproductive effects of PCBs have been noted in many mammalian and avian species. The pattern of reproductive effects include alterations in estrus cycles, failure of implantation, increased frequency of spontaneous abortions, low birth weight offspring HONS 22l*** and decreased post-natal survival. No specific teratogenic effects of PCBs have been observed In a variety of avian species. Transplacental effects, however, have been documented in both animals and humans (see Section VO). PCBs given to mice for 10 weeks at dosage of 1.0 mg/kg/day lengthened the estrus cycle by more than two days and decreased the number of successfully implanted ova (Orberg and Kihlstrom, 1973). Similarly, mice that received PCBs as sucklings in a long-term transgenerational study showed subsequent alterations In estrus cycles, decrease In implantations, and when mated to eadi other (Fl studies), reduced number of offspring per litter (Klhlstrom et ab, 1973). In rats, studies suggest that reproductive effects of PCBs decrease as chlorination Increases. No reproductive effects have been found with Arodor 1260 (60 percent chlorination) at 1, 10, 100 ppm, but significant effects have been noted with Aroclor 1242 and 1234 (42 and 34 percent chlorination, respectively) at doses of 20 and 100 ppm. Aroclor 1260 began to exert toxic effects at doses of 300 ppm. Rats chronically fed from 20 to 100 ppm Aroclor 1242 and 1234 had reduced numbers of offspring. Surviving newborns showed increased mortality, with only 30 percent surviving to weaning. Five ppm of either Arodor 1242 or 1234 produced no effects over two generations. Thus, the minimum effective doses ranged from 20 ppm for the lower chlorination mixtures to 100-300 ppm of the more highly chlorinated compounds (Keplinger et aL, 1971) Linder, et aL, 1974). Evidence of adverse reproductive effects is also available for nonhuman primates. Rhesus monkeys fed 2.3 and 3.0 ppm Arodor 124S for IS months in the diet showed dianges in menstrual cydss in addition to other systemic signs of toxidty. Evidence was also obtained tor frequent resorptions and spontaneous abortions following breeding - 16 - MOWS 221447 to normal male*. In all* six infants were carried successfully to term out of 1* pregnancies. The offspring were of low birth weight and by two months began to show evidence of PCB toxicity, presumably from PCB* in the maternal milk; only three Infants survived to six months. Behavioral tests in the three sirvivjng animals showed marked deficits In several learning tasks, with increasing errors correlated with Increasing body borders of PCBs (Allen and Barsotti, 1976; Bowman at al.. 1978) Barsotti et aU, 1976). The effect of PCBs on the male reproductive system is not known. There is one report of four male Rhesus monkeys exposed to 3.0 ppm Arodor 124S In the diet for IS months. After 12 months, one of four animals developed clinical sipu of PCB Intoxication, showed marked sperm count depression and was functionally sterile. A testicular biopsy revealed a marked decrease in spermatogonia. A second biopsy one year after exposure showed complete recovery (Alien et ai. 1979). PCBs are negative In the mouse sperm morphology assay (Heddle and Bruce, 1977). Comments PCBs show significant effects on reproductive competence in a variety ol species. These effects increase in intensity with increasing dosage and decrease with increasing diiorinatian of the PCB isomers. PCBs do not appear to be mammalian teratogens. A reasonable explanation for most of the reproductive effects of PCBs could be based on their estrogenic activity (see below). PCBs have been detected in human semen (Dougherty et ai, 19S0), but there have been no studies of semen quality in relation to PCB exposure in humans. The ellects of PCBs on the male reproductive system in animals or humans has not been adequately 17 - HONS 221448 studied. The only other evidence to date on reproductive toxicity in humans come from the Yusho incident and is summarized in Section VII. Other 1. immunosuppressive Efleets A number oi reports implicate PCBs as lmimnosuppressants (Fishbein, 1974). Lymphoid atrophy has been observed in rabbits, chickens and guinea pigs. Suppression of humoral immune responses to several antigens was observed in rabbits and guinea pigs, and decreased cell-mediated immune response followed PCB expos ire in guinea pigs. A decreased tolerance to hepatitis virus was seen in ducklings without apparent intoxication, in monkeys exposed transplacentally and through contaminated milk, the lymph nodules of the spleen were extremely small and without germinal centers (Allen and Barsotti, 1976)j morphologic changes were indicative of reduced imrmnologic compe tence. 2. Endocrine Effects Subcutaneous administration of A rodor compounds with lower chlorination produced an estrogenic effect on the rat uterus which was not shown with Aroclors of hitfter chlorination (Bitman and Ceal, 1970). Female monkeys fed A rod or 124S for six months showed an increase m concentration of ixInary ketosteroids and a prolongation of their menstrual cycles with Increased bleeding (Barsotti et aL. 1976). Antiandrogemc effects have been described in birds although the mechanism is not dear. It may be secondary to an increased rate of androgen metabolism in the liver by induction of microsomal enzymes (see Section VI), or by virtue of PCBs exerting estrogenic effects. IS HONS 221449 Comments The effect of PCB expo*ire on imrmne and endocrine system function has not been carefully studied in humans, so the relevance of these animal observations to human health remains inknown. There Is one cross-sectional study of occupational expos ire to PCBs which wilt include analysis of serum hormone levels and urinary metabolites, but resultt have not yet been published (Selikoff et al.. in progress). - 19 - HONS 221450 V. CARONOGENiaTY/MUTACENiaTY Cardnotcnicity Several PCB mixtires are dearly carcinogenic in rodent bioassays, producing liver tumors (hepatocellular carcinomas). Kanechior 300 and Arodor 1234 are carcinogenic in male mice (Ito et al., 1973; Kimbrough and Linder, 1974); and Arodor 1260 is carcinogenic In separate studies in two strains of female rats (Kimbrough et al.. 1973; Norback et aL. 1980). In addition, a purified component of a PCB mixture, 2,4,3,2*, 4', V -hexachlorobiphenyl, has recently been foind to be cardmgenic In female rats, causing hepatocellular cardoomas (Norback et aL. 1980). Because high doses of PCBs are known to cause extensive Injiry to liver tissue it is Important to consider the dose levels at which liver cardnomas were produced in the rodent bloassays. In two studies in rats, significant increases in hepatocellular cardnomas were present at doses which did not produce gross histologic changes. Hepatocytes were somewhat enlarged (probably due to microsomal enzyme induction), but no extensive fatty Infiltration or necrosis occurred, as was characteristic of bioassays at higher dose levels (Kimbrough et aL, 1973). Test Results 1. Mica (Male) A. Kanechlor 300, 400, and 300 fed to groups of 12 eight-week-old male ml as at 100, 230, and 300 ppm in the diet for 32 weeks produced hepatocellular carcinomas in 3 of 12 strvivors in the high dose group led Kanechior 300. The remaining 7 mice in this group had nodular hyperplasia (neoplastic nodules). No metastases or other tumors were - 20 - HONS 221451 present in this or other dosed groups. The control group ( mice) was likewise tumor-free (Ito et aL. 1973). B. A rodor 1234 administered to groups of 30 five to six-week-old male BAl.fi/c3 mice at dietary levels of 0 or 300 ppm (about 30 mg/kg body weight during the exposure) for 11 months produced neoplastic nodules (hepatomas or hyperplastic nodules) in 9 of 22 strvivors in the dosed group. Other liver lesions (adenofibrosis) were present in all 22 survivors. Additional morphological changes in the livers ol these animals inducted pleomorphism and areas of necrosis. Such changes and turnon were absent among strvivors (24) in the control group (Kimbrough and Linder, 1974X Rats A. Kanechior <>00 administered to ten-week-old Donryu rats (10 males and 10 females) at dietwy levels which varied from 40-600 ppm during the 400-day study produced liver tumors (multiple adenomatous nodules) in 6/10 treated female rats. Such lesions were absent from the controls (3 males and 3 females) and the treated males (Kimera and Baba, 1973). B. Kanechior 300, 400, or 300 administered to groups of 30 eight-week-old male Wlstar rats at dietary levels of 0, 100, 300, or 1000 ppm produced Increases in the incidence of cholangiofibrosis at the highest dose level of all Kanechlors (2/13, 2/10, and 4/13, respectively). All three compoinds also produced hepatic nodular hyperplasia, the incidence of whitfi increased with dose and extent of chlorination (Kanechior 300 at - 21 - MOWS 221452 100 ppm; 1/22; Kanechlor *00 at 100 ppm; 2/16, and 1000 ppm; 3/10; Kanechlor 300 at 100 ppm: 3/23, at 300 ppm; 3/16, and at 1000 ppm: 3/13)i (Ito at aL. 197*). C. Arodor 1260 administered to groups of 200 three to lour-week-old female Sherman rats at 0 and 100 ppm in the diet (varying between 3-10 mg/kg body weight during the 21-month exposure) produced at 23 months among the dosed sirvivors clearly significant increases of hepatocellular carcinomas (controls 1/173; dosed group 26/1 84) as well as neoplastic nodules (hyperplastic nodulesi controls 0/173; dosed group 1*6/184). The incidences of nonhepatic tumors did not differ between the dosed and control groups (Kimbrough et al., 1973X D. Arodor 1234 administered to groups of 2* eight-week-old Fisher 3*4 rats of either sex at dietary levels of 0, 23, 30, or 100 ppm for 103 weeks was not carcinogenic to any of the treated groups under the test conditions. It is important to note that two of the dose levels used were lower than those which produced a positive response in Sherman rats. Rare adenocarcinomas and carcinomas of the gastrointestinal tract appeared in both sexes and may be related to the administration of the PCBs (males: historical controls 6/600, dosed group 2/2*). In addition a high incidence of hyperplasia was present among the dosed poups (males: controls 0/2*, low-dose 3/2*, mid-dose 8/24, high-dose 12/24; females; controls 0/23, low-dose 6/2*. mid-dose 9/22, and highdose 17/24); (NCI, 1978). - 22 - HONS 221453 E. Aroclcr 1260 administered to groups of 30 male and female SpragueDawiey rats at dietary levels of 0 and 100 ppm for 103 weeks was carcinogenic in female rats, causing significant increases in liver hepatocellular carcinomas (Norback and Weltman, 1980). F. A purified component of a PCB mixture, 2,*,5,2\6\5,-hexachlorobiphenyl administered to groups of 30 male and female Sprague-Dawley rats at dietary levels of 0 and 100 ppm for 103 weeks was carcinogenic in female rats, producing an increased incidence of liver hepatocellular carcinomas among the dosed animals (Norback and Weltman, 1980). Mutatenlcity PCB mixtures have not been observed to have mutagenic activity nor to measurably affect chromosomes in repeated studies using a variety of in vitro or in vivo test systems Evidence of genetic damage from PCBs in laboratory test systems including dvomotomal aberrations, nondisjinction, less of sex chromosomes or increased frequency of sister chromatid exchange has not been observed. Report of a weak effect of Aroclor 1221 and of a stronger effect of *-<hl<robiphenyl in Salmonella using PCBindueed rabbit liver homogenate as a liver activation system appears unfounded (Wyndham et ak. 1976). Firther attempts to repeat these results have been ^successful using a variety of Salmonella tester strains and liver activation systems (Katzenellenbogen and Ames, 1980} Safe, 1978). However, PCBs belong to the class of heavily chlorinated animal carcinogens, most of which are not positive in short-term tests for mutagenicity. Examples In this class Include dielcfrin, dilordane, kepone, mi rex, TCDD , chloroform, and carbon tetrachloride. MONS 2 21454i Whether this is beciuse the in vitro metabolic activation systems do not produce the same spectrum of metabolites that occur in vivo or because heavily chlorinated compounds such as PCBs are carcinogenic by nonmutagenic mechanisms is not known at this time. Validation of the carcinogenic effects in rodents is provided by a positive cell trans formation assay using C3H10T1/2 done eight mouse fibroblast cells in culture by two separate PCB mixtures (Aroclor 1254 and 1260) and a purified component 2,4,5,2',V,5' - he xachlorobi phenyl (Norback and Weltman, 1980). Comments A wide variety of PCB mixtures have been subjected to rodent cancer bioassays and to numerous in vitro and in vivo short-term tests for mutagenicity. Several ol these PCB mixtures are carcinogenic. None of the PCB mixtures are active in short-term tests for mutagenicity, a finding that holds true for most heavily chlorinated cardnogens. However, substantial confirming evidence for carcinogenidty is provided by positive cell transformation assays u4ng these same PCB mixtures. Thus, under OSHA published criteria, PCB mixtures should be considered Category 1 carcinogens. Both 1ARC (LARC, 197S) and EPA (EPA, 1978) have conducted that based on available animal data PCBs should be considered ss potential human carcinogens.* * Category li Human evidence or two positive mammalian bioassays or 1 positive mammalian bioavay with supporting resuits in short-term tests. C ate nory lb One positive maetmaiian bioassay. (Source: Occupational Health and Safety Letter VoL 9, No. 24 November S 1979) - 24 - MOHS 221455 VI. BIOCHEMICAL EFFECTS OF PCBs Enzyme Induction The principal biochemical effect of PCBs is the stimulation and induction of certain enzyme systems. Enzyme induction occurs in both the microsomal monooxygenase or cytochrome P-450 system and the aryl hydrocarbon hydroxylase or cytochrome P-448 system, and It has been observed in both man and experimental animals. Induction is not restricted to the liver. It occurs In numerous other organs including kidiey, adrenal, ling, gut, skin, and testes. Fetal enzyme induction may occur via transplacental exposure, and induction may also occur by exposure to contaminated milk (Alvares and Kappas, 1975V Identification of structure-activity relationships for enzyme induction is difficult because of the large number of isomers in commercially prepared PCBs and because all commercial products contain trace amounts of polychlorinated dibenzofurans (PCDFs) which are orders of magnitude more potent os enzyme inducers than PCBs (Matthews et oL. 1978). In early studies using commercial Arodor*, potency for enzyme induction was found to be dependent an chlorination of the PCB mixture. Later, when purified isomers were tested, potency was found to vary with the position of chlorine atom substitution (Ecobichon and Comeaut 1975; and see Section IU). Since rate of metabolism is also known to vary with isomeric configuration of the PCB molecule, it may be that potency far enzyme induction is simply a function of the relative rate of metabolism and excretion. MONS 221456 The enzyme induction properties of PCBs are utilized in the metabolic activation system of in vitro bioassays for mutagenicity. It is unlikely, however, that enzyme induction would consistently enhance the effects of carcinogens or pro-carcinogenst it might function synergistically to activate a chemical, but they also might function to deactivate reactive carcinogens. Both phenomena have been observed in rodent cancer bioassays. Porphyria Porphyria cutanea tarda (PCT) in humans is an acquired defect in hepatic porphyrin metabolism characterized by uroporphorinuria, photosensitivity and mechanical fragility of the skin. PCT can be produced experimentally by a number of (tugs, including tetrachlorodibenzodloxins and PCBs. All of these agents have the ability to stimulate the activity of 2-ami noievuiinic acid (ALA) synthetase which is the initial enzyme in the heme synthetic pathway. Experimental hepatic porphyria was observed in Sherman rats exposed to Aroclor 1254 in the diet. At doses of 100 ppm the animals became porphyric after a delay of approximately 2-4 months. The porphyria resembled hex*chlorobenzene poisoning and human PCT (Goldstein et al,, 1975L In chronic feeding studies ALA-synthetase induction occurs after rats have become porphyric, although with large single doses the enzyme induction is seen almost immediately after dosing the animals (Goldstein et aL, 1975). It has not been established whether only certain isomers in the PCB mixtures or - 26 - MOMS 221457 contamination with PCDF* is responsible for the production of hepatic PCT. Porphyria has not been reported in humans exposed to PCBs. Comments Enzyme induction has two important implications for human health) 1. the occurrence of disease secondary to the increased metabolism of endogenous or exogenous substances, and 2. the interference with medical therapy due to increased metabolism of administered ctugs. PCBs are more potent enzyme inducers than phenobarbital, a drug that occasionally causes clinical problems due to Id enzyme Inducing effects. While the effects of phenobarbital decline after administration ceases, enzyme induction from PCBs persists long after cessation of exposure. - 27 MOMS 221458 Vfl. HUMAN TOXICOLOGY AND EPIDEMIOLOGY Few good epidemiologic studies of the health effects of PCBs are available. Most studies reported in the literature have been characterized by one or more of the following shortcomings! 1. small study populations, 2. lack of accurate exposure data, 3. simultaneous exposure of workers to other potentially harmful chemicals, 4. lack of control for confounding variables, such as alcohol consumption, and 3. inability to separate PCBs from contaminants ahd/or difficulty in comparing PCBs manufactured by different firms. In spite of these problems, some health effects have been consistently reported in studies of workers occupationally exposed to PCBs. In addition, a large-scale poisoning whldt resulted from ingestion of PCB/PCDF-contammated rioe oil has been well documented and resulted in multiple signs and symptoms attributable to PCBs and/or PCDFs. The health effects identified in a review of the epidemiologic literatire are summarized below, and Table II briefly describes the major epidemiological studies from 1934 through 1980. Dermatologic Changes Chlcracne, contact or allergic dermatitis, and brown chromodermatosis have been consistently reported In studies of workers exposed to PCBs (Hara et aL. 1975; Hasegawa et aL, 1972; Inoue et al., 1975; Kitamura et aL, 1973; Baker et al,, 1980; Meigs et &1., 1934; Ouw et al., 1976; Schwartz, 1936). - 28 - MOWS 221459 Systemic Symptoms Nausea, digestive disturbances, headaches, upper respiratory problems, and persistent body odor have been reported as a resuit of occupational exposures (Ouw et al., 1976; Schwartz, 1936; Wanhaw et al., 1979). Liver Damage Abnormal liver function tests have been reported In a number of occupational studies and clinical hepatitis was observed in the Yusho epidemic. However, some of the earlier Investigations reporting abnormal liver faction did not control for exposure to additional chemicals, previous medical history or drinking pattern and some of the marginal differences observed could have been related to these confounding variables. More recently, Fischbein et al., (1979) louid no significant differences in LFTs between capacitor manufacturing workers with low level chronic exposire and nonexposed controls. However, in a cross-sectional survey by Maroni et aL, (1981 a & b) abnormal LFTs were observed and seemed to correlate with serum PCB levels. With the exception of a few cases of diloracne, these workers had no other symptoms, signs or laboratory abnormalities. Yusho (Japanese word translated as "oil disease") Both dermal and systemic health effects are well documented in the epidemiologic study of a poisoning epidemic in Japan caused by ingestion of contaminated rice oil in 1961 (Higuchi, 1976; Kuratsuie et al., 1972). - 29 - MOHS 221460 It is not clear how much the health effects observed in Yusho victims can be extrapolated to occupational exposures for the following reasons: 1. The average amount of PCS (Kanechlor 400) ingested was estimated to be 2 grams and the minimum, 0.5 gram (Kuratsune eta]., 1972). This is a higher dose than has been reported in most occupational exposures. In addition, the PCBs were ingested as opposed to inhaled or skin-absorbed as is the case with occupational exposures. 2. The contaminated oil contained "used" Kanechlor 400, the exact chemical compositon of which is unknown. 3. Frying of foods with the rioe oil could have produced new compounds which may have altered the toxicity of the PCBs or the toxicity of possible contaminants. 4. Yuaho oil was shown to contain high concentrations of dibenzofurans. 5. Reported concentration of PCBs in the oil may not have been accurate enough to permit a rigorous quantitative analysis since the methods for estimating PCBs in foods were not fully developed at the time. Clinical features of the Y usho patients are listed in Table III. The Y usho incident is also important because it clearly documents the potential for reproductive and transplacental effects in humans. A study was made of the 13 infants of 11 mothers affected by Yusho and of 2 unaffected wives of patients: 2 of the Yusho mothers had stillbirths; 10 of the babies had transient greyish or dark-brown pigmentation of the skin, and 5 had similar pigmentation of the gingiva and/or nails; increased ocular discharge was present in 9; and 12 of the 13 Infants were small when compared with the national average (Fuiatsu et aL, 1972t Kikudti et aL. 1969; Kuratsine, 1976j Taki et aL, 1969). Babies born to patients even 3 years after severe PCB exposure tended to show pigmentation of the skin on the back and the gingiva, although the degree of pigmentation was less than that of babies born to the same mothers up to one year after the poisoning (Kuratswe, 1976). - 30 - MOMS 221461 Congenital abnormalities have also been observed in PCB-mtoxicated infants. In the population of 13 offspring of Yusho mothers, premature eruption of teeth was observed in 2 cases, and larger than normal frontal and occipital fontanelles, exophthalmos and the persistence of an abnormally wide sagittal suture were observed in 3 others. No other gross malformations were reported nor was any relationship between dose and outcome considered (Funtasu et ah. 1972). Mothers' milk contaminated with PCBs also appears to be a source of exposure for infants* one baby showed signs of poisoning even though the mother had ingested the contaminated rice oil only after the baby was delivered. The infant began to show signs of PCB Intoxication after 3-4 months of breast leeding (Kuratsune, 1972; Yoshimura, 1974). Neurotoxicity Paresthesias were reported in over 30% of Yusho patients (see Table 111), In the Yusho epidemic more detailed neurologic examinations were performed in 21 cases admitted to a university hospital in northern Japan. Ten of the patients complained of numbness or pain in the distal extremities, and in five cases decreased pain, touch and temperature sensations were observed. Sensory conduction velocity in sural and radial nerves was below normal In 6 of 10 individuals with neuropathic symptoms (Mural and Kuroiwa, 1971). A decrease in amplitude of muscle action potential evoked by nerve stimulation, and a decrease In sciatic nerve conduction velocity has been reported in rats intoxicated with tetrachlorobiphenyl. Thus, PCBs can affect peripheral nerve function in both - 31 - MONS 221A62 humans and experimental animals, but these have been reported only at doses which cause other systemic signs ol poisoning. Cancer There is too little epidemiological evidence available yet to evaluate the potential ol PCBs as human carcinogens (Bahn et al., 19SQ; Brown and Jones, 19S0). A loliow-up of the Yusho patients through 1977 has reported 51 deaths (31 with cause of death confirmed) of the 1,66? identified victims. There were 11 deaths from neoplasms, or 35.4% of the total. While this rate is higher than the 21.1% in the population of the same prefecture in 1977, these data were not age>adjusted. No particular site was elevated, and there were no deaths from malignant melanoma, a tumor previously suspected to be linked to PCB exposure (Bahn et al., 1974). Two liver cancers and two lung cancers were reported but smoking and drinking patterns were not available (Urabe et al. 1979). A retrospective cohort mortality study of 2,567 workers in two capacitor manufacturing plants was recently completed by NIOSH. The report did not find any statistically significant SMR for any cause of death among exposed workers. Deaths from liver cancer, cirrhosis of the liver and rectal cancer were slightly higher than expected, though these excesses were not statistically significant and no information was available on medical histories, drinking patterns, etc. There was no relationship between increased mortality from all causes of cancer, rectal cancer or liver cancer, and length of exposure to PCBs. Limitations in the study design, however, might have obscured a true association. In particular, there was a relatively small sample followed over time thereby limiting the statistical power of this study. Second, there were on the average - 32 - MONS 221463 only 15.19 years ol follow-up for each exposed worker in the study. Usually the latent period between exposures and deaths from cancer is longer. Third, exposure to PCBs w*s quantified for March 1977 only} there was no data on actual PCB exposures during the time when most of the population at risk was working with PCBs. Finally, over JQ% of the sample has exposure to PCB for only two years or less. Oneoinn Occupational Studies Two additional cohort mortality studies are currently underway. The first is a mortality survey of the entire workforce employed between 1952*1957 at the largest United States' facility that manufactured capacitors and transformers. There is detailed information available on exposure leveis in the plant. While the duration from onset of exposure is shorter than optimal (only 25 years in some cases), the information will at least give data on the short-term mortality experience of a heavily exposed occupational group (Selikoff et aL, in progress). The second is a similar occupational mortality study, also of workers exposed in capacitor and transformer manufacturing. Over 2,000 workers have been identified for this study but no father details are yet available (Bertazzi et al.. in progress). One case control study is currently being conducted to assess whether there is excess risk of malignant melanoma among PCB-exposed workers. This data will not be aviilible until March, 1982 (Bahn etal., 1976). - 33 - MONS 221464 There is also one cross-sectional clinical field survey of 326 capacitor manufacturing workers at two sites* encompassing a total workforce of 100 (Fischbein et al., 1979), Exposures were classified as none, low, medium, and high based on job description at the time of the survey (1973). Researchers were able to identify the PCBs used and had some data on environmental air levels in the plants. A number of parameters were measured, including complete history and physical examinations, SMA panels and pulmonary function tests. Results have been published on respiratory function (Warshaw et a!.. 1979) and general signs/symptoms, and results of serum lipids, endocrine function and dermatologic findings are forthcoming. To date, the only positive association .# involves dermatologic signs and symptoms. Further Investigations of the effects of PCB exposure on serum lipids have been done in both occupational and general environmental exposure settings. Smith et al., (197S), reported some statistically significant differences between exposed and nonexposed workers at two sites. They reported higher serum triglycerides and lower levels of high density lipo-proteins in the exposed group. Whether the magnitude of the difference is biologically significant is not clear from this study. For example, the nonexposed group at site #1 compared to the nonexposed group at site 02 showed a greater difference than the exposed and nonexposed comparison at either site. In another study (Baker et al,, 1980) workers and community residents with exposure to fertilizer * Warshaw et aL (1979) concluded that there was also an association between PCB exposure and impaired pulmonary function (restrictive pattern). However, there were major methodologic problems with the data: the particular spirometer used (heated wire flow sensor) is notoriously inaccurate; it was not possible to link exposure data with particular PFT results; there was no information on race, and finally the magnitude of the observed etCects was low and no statistical comparisons were done with nonexposed controls. - 39 made from sewage sludge contaminated with PCBs were studied. Plasma triglyceride levels were found to increase significantly with serum PCB concentration (both m drinkers and nondrinkers), and the authors concluded that PCBs may alter lipid metabolism at levels of exposure and bioaccumulation insufficient to produce other identifiable signs of toxicity. Comments Although many problems have been identified in the studies evaluating the health effects of PCBs, it is clear that occupational exposure, at a minimum, can produce dermatologic effects. The long half-life of PCBs and their bioaccumulation in various human tissues leaves open the possibility of substantial chronic and delayed eflects analogous to those seen in animal bioassays. These effects have only recently begun to be studied In a rigorous manner, and although the epidemiological evidence is neither complete nor entirely consistent there can be no question of the necessity to protect the worker from exposure. 35 MOMS 221466 VIII. MEDICAL SURVEILLANCE AND BIOLOGIC MONITORING Medical surveillance and biologic monitoring are of limited usefulness in predicting health hazards if dose-response relationships are not known. This certainly is the case with PCBs. Based on animal toxicology, there are many suspected adverse effects of PCBs which might result from exposure in occupational settings, but very few have been documented well enough to give even rough estimates of "no-effect" or "safe" levels. A large percentage of nonoccupationally exposed people have detectable PCB levels in body fat, blood and milk. However, any attempt to estimate an adverse health effect associated with increases above this background level necessarily involves extrapolation from animal data and, therefore, is subject to considerable error, especially when the marked variation in sensitivity of various animal species is appreciated. Furthermore, not enough is known regarding the relative dose-response characteristics of the various documented effects (e.g., liver damage, skin changes) to state that in the absence of a particular sign, symptom or laboratory abnormality, the risk of long-term effect (cancer, reproductive toxicity) will be negligible (see Table I). For the clinician confronted with a worker who has a history of exposure to PCBs the approach to management cannot be easily outlined. Given the current analytic methodology, residues can be measured in blood or tissue in the ppb range and compared to background; but assigning a health risk to a given level is virtually impossible, especially given the lack of pharmacokinetic data. Often patients are being evaluated niter a considerable lag period (years) since last exposure occurred and extrapolation to peak blood levels is not possible. In fact, it may be that residue levels bear little relationship to the health risk. For example, the lower chlorinated compounds may be more toxic but they are more rapidly metabolized and excreted and, therefore, less likely to persist in blood or fat. Further, with the possible exception of chloracne, - 36 - HONS 221467 the presence of specific signs, symptoms or laboratory abnormalities is very difficult to definitely relate to PC8 exposure in any given patient. Given these uncertainties and the potential for serious health effects, the approach to monitoring should emphasize environmental sampling and every attempt should be made to minimize exposure by engineering controls or personal protective measures in those settings where occupational exposure still occurs (e.g., utility repair workers). Biologic monitoring may be used to assess the effectiveness of environmental control, but it is really best utilized within a specific research protocol and probably has little value in the routine work-up of individual patients. - 37 NONS 221468 SUMMARY AND CONCLUSIONS PCBs have low acute toxicity but are of public health concern because of their perjistence in the environment and in human tissues and their demonstrated potential for chronic or delayed toxicity. They are potent inhibitors of reproductive function in both rodents and nonhuman primates and are positive in animal cancer bioassays. As potent inducers of hepatic enzyme systems, PCBs may have additional unpredictable long-term health eflects. Some ol the conflicting reports in the toxicology literature are undoubtedly related to the variable composition and trace chemical contamination of the tested mixtures. Occupational end environmental exposure is usually to those mixtures; but if we are to accurately assess the associated health hazards, further animal studies are needed which carelully define the toxicology of the individual agents. Epidemiologic studies of occupational exposures to PCBs to date have failed to detect serious adverse effects but are considered insufficient, and further studies are clearly needed. Of particular interest is the continued exposure among utility workers. Because of the potential ability to cause cancer and other long-term adverse effects such as infertility and hepatic injury, human exposure to PCBs should be kept to the lowest level technically possible. The persistence of PCBs in the body and the irreversibility of some of its effects make it necessary to act now, rather than to wait until more definitive data are available. -- MONS 221*69 REFERENCES ACG1H. Chi orodl phenyl - 42% chlorine, Documentation of the TLV* for substances in workroom air. 3rd ed., pp3l-2. Cincinnati, 1976. Albro, PW and Fishbein L. Intestinal absorption of PCBs in rats. Bull Environ Contam Toxicol 8; 26, 1972. Allen, JR and Abrahamson, LJ. Morphologic and biochemical changes in the liver of rats fed PCBs. Arch Environ Contam Toxicol ^1:263, 1973. Allen, JR. Response of the nonhuman primate to PCB exposure. Fed Proc 34:1673, 1973. Allen, JR and Barsotti, DA. The effects of transplacental and mammary movement of PCBs on Infant rhesus monkeys. Toxicol 6:331, 1976. Alien, JR et al Response of rats exposed to PCBs for 33 weeks. Arch Environ Toxicol 4:4S5TT976. Allen, JR et aL Reproductive effects of halogenated aromatic hydrocarbons on nonhuman primates. Ann NYAS 320:419, 1979. Alvares, AP and Kappas, A. Induction of aryl hydrocarbon hydroxylase by PCBs in the retroplacental unit and neonatal livers during lactation. Fed Europ Biochem Soc Letters 30:172, 1973. Anderson, MW et al. The construction of a pharmacokinetic model for the disposition of PCBs in the rat. Clin Pharm Therap 22:763, 1977. Bahn, AK et ai. Melanoma after exposure to PCBs (letter to the editor). N Engl J Med 293:430976. Baker, E et aL Metabolic consequences of exposure to polychlorinated biphenyls (PCB) in sewage sludge. Amer J Epldm J_[2:333, 1980. Barsotti, DA et aL Reproductive dysfunction in rhesus monkeys exposed to low levels of PCBs (ArocI3T 1248). Food Cosmet Toxicol .14:99, 1976. Bertazzi, PA et aL Mortality experience among PCB workers. Univ of Milano, Inst Occ Health, Milan, Italy, in progress. Bitman, J and Ceal, HC. Estrogenic activity of DDT analogs and PCBs. J Ag Food Chem J8H1Q8, 1970. Bowman, R et al. Correlation of PCB body burden with behavioral toxicology in monkeys, pharmocol Biochem Behav 9:49-36, 1978. - 39 - HONS 221470 Brackner, JV et al. Biological response of the rat to PCBs. Tox Appl Pharm 24:434, 1973. Brown, DP and 3ones, M. Mortality and industrial hygiene study ol workers exposed to polychlorinated biphenyls. Draft report, NIOSH Division of Surveillance, Hazard Evaluation and Field Studies 1950. Bumgarner, 3E et al. Polychlorinated biphenyl residues in refuse workers. National Institute of Environmental Health Sciences (as reported In NIOSH Criteria Document), 1973. Burse, VW et aL PCBs - storage, distribution, excretion and recovery: liver morphology after prolonged dietary Ingestion. Arch Environ Health 29:301, 1974. Curley, A et aL PCBs - distribution and storage In body fluids and tissues of Sherman rats. Environ Res 4:4S1, 1971. Curley, A et aL PCBs evidence of transplacental passage in the Sherman rat. Food Coam Toxicol l_l:47i, 1973. DHEW: Subcommittee on health effects of PCBs and PBBs - series of articles appearing In Env Health Persp 24:146-195, 1975. Dougherty, RC et al. Sperm density and toxic substances: a potential key to environmental health hazard, submitted to Env Health Chem, 19S0. Ecobichon, DJ and Comeau, AM. Isomerically pure chlorobiphenyl congenes and hepatic function in the rati influence of position and degree of chlorination. Tox Appl Pharm 33:94, 1973. EPA: Halogenated polyaromatics, m: L Fishbein, Potential industrial carcinogens and mutagens, pub #560/3-77-X3, Office of Toxic Substances EPA, Washington, DC ppl73197, 1977. Finklea, 3 et aL PCB residues in human plasma expose a major urban pollution problem Amer 3 Public Health 62: 643, 1971. Fischbein, A et iL Clinical findings among PCB-exposed capacitor manufacturing workers. AmWAS 320: 203, 1979. Fries, GF. PCB residues in milk of environmentally and experimentally contaminated cows. Env Health Persp. _l*55f April 1972. Funatsu, I et al. Polychlorobiphenyls (PCB) induced fetophathy. 1 Clinical observation (Abstract No. 72-2360). Kurume Med 3 _19:43-31, 1972. Gardner, AM et__aL PCBs hydroxylated urinary metabolites of 2,3,2\3'-tetrachlorobiphenyl identified in rabbits. Biochem Biophys Res Comm 33:1377, 1973. Goldstein, 3A et al A comparative study of two PCB mixtures on induction of hepatic porphyria and drug metabolizing enzymes. Tox Appl Pharm 32:461, 1973- - 40 - HOWS 221671 Grant, DL et tL Metabolism ol PCB (Aroclor 1254) mixture in the rat. Bull Environ Contam Tox 6; 102, 1971. Hara, 1 ct aL Foliow-p study of condenser factory after use of PCB discontinued. (As reported NIOSH Criteria Document) Jpn J Ind Health J7:371-372, 1973 (Jap). Hasegawa, H et aL Report on survey of work area environment where PCB is handled and of this health of verkers handling PCB, in special research report on prevention of environmental pollution by PCB-like substances. 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PCB level in blood serum of laborers and results ol physical examination (as reported in NIOSH Criteria Document) Jpn. 3 Public Health .22:1637, 1973 (Jap). Ito, N et al. Histopathologieal studies on liver tumorigenesis in rats treated with PCBs. Gann 63i543, 197%. Jensen, S and Sundstrom, G. Structure and levels of most chlorobiphenyls in two technical PCB products and in human adipose tissue. Ambio 3:70, 1979. Jerina, DM and Daly, JT. Arena oxides: a new aspect of drug metabolism. Science ,165:573, 1974. Kar ppanen, E and Kolte, L. The concentration of PCB in human blood and adipose tissue in three different research groups. In, PCB Conference 11, Stockholm 1972 (as reported in NIOSH Criteria Document) Sona, Sweden National Swedish Environment Protection/PubUcations, 4E, pp 124-12S, 1973. Katzeneilenbogen, J and Ames, BN. Personal communication, i960. Keplinger, M et al Taxicologic studies with PCBs (abstract). Tox Appl Pharmocol ,19:402-403, 19717" Kihlstrom, JE et al. Sexual function of mice neonatal!y exposed to DDT or PCB. Environ Phys Biochem *54, 1975. MOMS 221A72 - 41 Kikuchi, M et al. An autopsy case ol stillborn of chlaro biphenyls poisoning, Fukuoka Acta Med 60:419, 1969. Kimbrough, RD et aL Morphologic changes in liver of rats led PCBs. Arch Ind Health 23:354, 1972. Kimbrough, RD. The toxicity ol polychlorinated polycyclic compounds and related chemicals. Crit Rev Toxicol 2:443, 1974. Kimbrough, RD and Linder, RE. Induction of adenofibrosts and hepatomas of the liver In BALC/cJ mice by PCBs (Arolcor 1234). 3 Natl Cancer Inst ,33:347, 1974. Kimbrough, RD et aL Induction of liver tumors in Sherman strain female rats by PCB (Arocior 1260). "TNatl Cancer Inst 33:1433, 1973. Kimbrough, RD et al. Animal toxicology, DHEW Subcommittee on Health Effects of PCBs and PBBs. Env Health Persp 24:173, 197S. Kimbrough, RD. Chronic toxicity of haiogenated biphenyls and related compounds in animals and health elfects in humans. Presentation at the American Chemical Society meeting, August 19S0. Las Vegas, Nevada. Kimura, NT and Baba, T. Neoplastic changes in the rat liver induced by PCB. Gann 64:103, 1973. Kitamura, M et aL PCB in blood of workers employed in an electrical parts manufacturing plant. (As reported in NIOSH Criteria Document) 3pn 3 Ind Health _13:339, 1973 (3ap>. Kiratsine, M et al. Epidemiologic study on Yusho, a poisoning caused by ingestion ol rice oil contaminated with a commercial brand of PCBs. Environ Health Persp lii 19, 1972. Kutz, FW and Strassman, SC. Residues of PCBs in the general population of the U.S. Proceedings ol the national conference on PCB, Chicago, EPA-360/6-73-004, Washington DC, pp 139. Linder, R et aL The effect of PCBs on rat reproduction. Food Comet Toxicol J2:63, 1974. Lutz, R3 et aL Preliminary pharmacokinetic model lor several chlorinated biphenyls in the rat. Drug Metab Dis 5*386, 1977. Maroni, M et aL Occupational expos ire to PCBs in electrical workers 1. 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Nelson, N et aL PCBs - environmental impact. Environ Res 3:209, 1972. NIOSHi Criteria for a recommended standard - occupational exposure to PCBs NIOSH, Cincinnati, 1977. Norback, DH and Weltman, R. Personal communication 1980. New York State Health Planning Commission. Report of the ad hoc committee on the health implications of PCBs in mothers? milk. Albany Health Advisory Council, 1977. Oishi, 5 et aL Comparative toxicity of PCBs and dibenzofurans in rats. Tox Appl Pharm 43:13, 1978. Orberg, 3 and Kihistrom, 3E. Effects of long-term feeding of PCB, Clophen A-60 on length of estrus cycle and frequency of implanted ova in the mouse. Environ Res 6:176, 1973. Ouw, HD et aL The use and health elfects of Aroclor 1242, a polychlorinated biphenyl, in an electrical industry. Arch Environ Health 31:189, 1976. Sato; M and Hasegawa, H. Amount of PCB in blood of laborers. (As reported in NIOSH Criteria Document) 3pn 3 Ind Health .16:363, 1974 (3ap>. Safe, 5 et al The metabolism of 4-chi orobiphenyl in the pig. Can 3 Phys Pharmacol 33:392, W1. Schwartz, L. Dermatitis from synthetic resins and waxes. Dermatitis 26:386, 1936. Selikoff, 13 et aL Mortality experience ol factory workers exposed to PCBs in the manufacture of transformers and capacitors. Mt. Sinai School of Med, Env Sciences Lab, New York, NY, in progress, 1980. - 43 - HONS 221*74 Shiota, K. Postnatal behavioral effects of prenatal treatment with PCBs in rats. (As reported in IARC, 1978). Okajimas Fol Anat Jpn 33:103, 1976. Smith, AB et al. Lipid and lipoprotein alteration: occupational exposures to PCB. Clinical Res 26:349, 1978. Stalling, DL et af. An expanded approach to the study and measixement of PCBs and selected planar haiogenated aromatic environmental pollutants. Ann NYAS 320:48, 1979. Taki, 1 et al Report on Yusho (chiorobiphenyls poisoning)) pregnant women and their fetuses. ?j<uoka Acta Med 60:471, 1969 Pap). Treon, JF et al. The toxicity of the vapors of Arocior 1242 and Aroclor 1234. Am Ind Hyg Q .17:204, 1936. Urabe, H et aL Present state of Yusho patients. Ann NYAS 320:273, 1979. Vodiauk, MJ and Lech, JJ. The transfer of 2,4,3,2>,4',5,-hexachiorobiphenyl to fetuses and nursing offspring. Tox Appl Pharm 34:293, 1980. Van Miller, JP et aL Distribution and metabolism of 3H-2,3,7,31-tetrachlorobiphenyi in rats. Proc SocXxp Biol Med 148:682, 1973. Vos, 3G and Beems, RB. Dermal toxicity studies of technical PCBs and fractions thereof in rabbits. Tox Appl Pharm J9:617, 1971. Warshaw, R et aL Decrease in vital capacity in PCB-exposed workers in a capacitor manufacturing facility. Arm NYAS 320:277, 1979. Wyndham, C et aL The in vitro metabolism, macromotecuiar binding and bacterial mutagenicity of 4-chlorobipKenyl, a model PCB substrate. Res Commun Chem Pathol Pharmacol _13i363, 1976. Yoshlmura, T. Epidemiological study on Yusho babies born to mothers who had consumed oil contaminated by PCB. Fukuoka Acta Med 63:74, 1974 Pap). - 44 - MONS 221*75 TABLE I Dii.uirani re* *imi reiicouoT bl tal bt bl bl Ui bt bi MU* Mu Mir Mif Mil IMmt M* Mali uMtla| MtiU Imilil Mull Mall Mill UiU 44*U **! Moll Mull *tW Mill* feaU Mill *< n Malt bUU bl, but, Ww *1*. Ml* Ml HIM **|t M*ill mb MU* bu ) Hill i Will bia bit 1 mb 1 ! b*t irnlt l*5*. i:m ArMltt t:s*. W40 imlH l.HI. mi, mi UMlM Ul'. in* AtmU* lutl 0r*l 0fl 0t*| 0vt bil **! um Mil IwUl 1U4 tat IMMIH HO tat Wa* rat ciipn* ** imlH It** Inin II** ImIw ll*t ImlH It** vat rat rat Oral Oral Imlm ttUlM* imlH 1H* *ncU* HI* IiiiiIm M* Nml bvul mat laMl* a rat imlat III* *i**M* UU Oral tal IrwtM 1140 Oral !,*.M> ,*'. ItiHlIirili* ***! tat b*i u^|/bt * io.oco trioo . UJOO w 10* 11 .* 1.* t.o T.O 1.* 1* 1.1 O.l-l* 0.00-0.11 HIM 70 *re . t.l #.l M 10 1* 1* to fatal bfillM 0**a Uf**l ltn|la t*r*r* but* tfi*** 4 mate 4 uib *** * "w not Uaat hm'tra**V, falt taflttraila* reo.uoo l*tl, Un* 1*13 4*f laatalla* 1 MltlH pftaf u MtlH t uttb atlav u uttu by l-U a* 19-11 lutatiM 4 w*M UrtlH (t kftl NO 1900 *00 *.* 100 allaprlot 4 Uttar ataa fuutfil affaptlao fwrulMr MltHla* M1IH k*k*l* *tl**fl** | vatlam lunlb aaftaja affair i*o oiiriMuiiM, mm iiii^dinim **** u him ir*tt<iMiui Kta*ra*th *t till Kta6vaa|h * i] 14*1 Allan 4 Mvafeman.t* lata* at a|, 1914 lintan t *| B + 1914 ItntM *t |*, 1914 Uataa at at*. 1914 Jhlatt, l*l Ikliiti* 11 (l mi Owll* I4hw 4 mat* MO Iwiiiwl ittm* *rtl<> iMbMUiw ul|kt lau, alaaacla, faaial tma, afa ttaaharta 00ar| 4 UhltlMt 191) itu*. mi 1 Ml too Un* 11*1*111111 (kt*uta*,l*l) ilia*, mi 1 Will 11*1100 bit*, |utrli alaavatlan, Allaa, 1919 facial Una, tfcynla acrapfcf 1 yut IM1 facial aOaaa, ilayuU aaaa, +fact||fttr, impilav tauaaa, tmly *Wattm- a/faatlaoi amlgac. bU itrMf*nua (caiaccaOla PCl'i la tlaaaa) *tu*. mi 11 *4f taola Uyutva it Mr* 1? Ml (MO H* 490 ilt,H*fi- llrar kliul**? tub m blartf i u tl 4a ya vtd tlaac lUtflf alia, Um a*i tliMf bu|o laraacaala lima 41* Mill.*, |M* NllUf, 1944 Vat 4 bNa, 19H Tram, ll 11 ***** W rmtilbU ll* 4 Tram, Hit 11 utba II. IT* 4a>acaaall|at uritMm <aaataal l/l| luH 9/M) f aaaataatla ublii tiHint 0/4* 4aaa4 1/it) tta at at., 191S ** ***** l*.l** <fw0laatla nblii <central 0/l4| taae* 9/11) 4 Un4, 1974 *1 nub .l tbutullitav untmu llabbtl at al (taatral |/iT)j 4a4 ta4/tl4) 1419 iMfftMlU MlltM <fuuii 0/11)| amat U/tH) 104 mb M ** +VMacMwlar otiImm* (maatltafcaO, 1400) b*tS at at** 1140 104 *tb fbiUutlUUr 4i*iMw (mUllaM, 1940) attach at #t* 19M * Mmt* wft lyiiH it 1 > w ttl *" |"h f>f t fat IT w<m( j fi 4*a* in iKt fittnlM (irttiiiMf mn aatltati 0*1 (! f lr hfMihN ^ m tf *U1 H 4*f>! 0.9 (mILiM < **U1 LA k)| |4/T 'ctPIUdM It** H l*f v taf/mat tmwi), ftnawtilna **U* t|MM| too*. V> * -VkJL Jam <* 5"*/*} -45- NONS 221476 mu II - occumiwu. ufoitiii to pci. ti-tr Hall* l*W> N4* bran *4 4arv tut* ta a #kMl*b plan Uptwtt lartl 4 T|*a It^T hfaUlia CmiU lanl tflcl* ! /_ rttltr- ) t* It *a*. 1*1 tr ail * Matora ttroi* rtftr Ittktit II otto tuny ttotti r M4 i# NMaraia cblirwM, tmm 4aratltU Ha#|aM 1 [** ItVtl lull al t latvaillal *1**1* lotiati* rci mo- iKHrlatt apli*r, nmiIkIMc at klfhaarl rmrr TlWlI TPWT at/ ) NriUviitiii ITOTTOW it t*in> (1 U M yurt tt M harlot U*K focllM t aiul, 1 OrMrllM ha*rati lllthtlr thaaiwl Dirt *1*1., Itrt-TTTTT ll*#7 mill m 1? iiMrilH Uvi *t mf--fflM rtprt4 J nm CilUfil lit )f| mmp rt^rt^ 111 itrU*iU* UMIaf* < CiMif/ CtMiMlillm NMtiUir Emm Ittaaati )' m to*>**** ro TVara m aac a |Ml carfalatlM batuaaa 4t|rn #f (aptnu aal Java laprub ( il|M #f 4U*m VruJ all mm* Mc a*r!ata* It kliat baar* aa ) plot*. iktrt w* M Cl latiothi* *r bt*Ml t* blM* (Mtf trniMi, in mbauii ippiriMir aff*cta4* 7-M M Klfcu *ra* lit#4 with 4vr- CIm *f ti^atrti N Wt l(M blMtf tMfMlla* t(*M MCI tfiM4 bjr **ry *| MwM*. TV# 1m|t (ba 4ra> Mm # KMNrt, tha lMgr Oia fC b*lfM!a C* blMtf. HONS iuu II* tcoriTiwu umimi to Kit (t*M'i) lllain l))i hill *1 wrkin U ii^hHii k*aa ittiafiti M**> imn Uni i) mi imiM n iiino cu ltru Ituiml M*ll 1.) ftt. trlaaai ten. aaktr'kaa, linn, tit. own) tmmm #*>> itrti H4r *f ft r**lir #>*>* 4rifti *iU ibr*4 |ImiU| ftfttftllftft* MM DIMM 1* IIMI Cll- ttrlt Itinat at Mir MtMn at* 1 **> (iuu H ** n****> mi (*>*) Ull Utiftft* ft* --titmmm ftft < * hcb ii (tit lat HaM|m t)4i rrttHtl M* 111*4 iirtw Iim pata* HllHIHir t.O - 4.4 a*/) M* .! 1.1* Ihimii i rtt. ftaa K> im) M HftiUt la *1H Crlttru bllNM* Mb* Itltt 1*111 14** > t im*it 1) m mtn 1) iMiriiui lak ntiata t) HNtlUt larrtfaatlaa tartar* (Arm la* 1141) kaa. Mils M Mk mm 4 1 nt*> t44k fell K* IWlHl no urmrn ( m1m 4 Intltt IMln IWMUH t lamlaa Ixitrur i ill* IfISl 1tZSf ft4 nlMi wriM tftftfttH t Kl U Iftfttft* ftffttiftft *4 ftltl lMlr#ii4 Wtl 1) M rtf* mkui Mm Afftft*( u* rrk m -no* Nti 110.1M tk Hull r*4 aatapaaaAl 10 nk INtfftrt> 1.4 - II N4Im M-4) * Ilk nwM )4.t,M* nk Htaaaraklt cmiitrillMt It It tf 4kt If rilm nrkttt (4-14 nkl M ratal Inaklp Mi (m Mam ntcnlnrM 1* kin. IM lalillii a* aataaaca. Km fttr fftMi 1ft Hthan* till m kititfit IImi Umimi. ClMMimlMI nt mi l ctrrtMltk -lit mat In a( iiimn. -tf NONS 221478 uau II* tCCvritioiUL antmt tch (tmt't) >1 *Ui HUXitUf it ttutlft MMlNtUff MfMMi AiKlir lltil l.l - 1.1 */.! (It *rh*r){" I.M mt/J (1) mlln) torhin intMtln llMItlf riM i M. to )) rto* H U*, 11 !.. itfu uwr f nitin U rillwrr KMlit IIH ttot 4 V |t frM }l hIm m4 41 (HIM Im h4 imu JHti Mirt mllt| Ml t IUHlM ihI nit riaai H M - Ml " rl it lit - UM </ t riMt ii Mt Mm* it l,W III It tr* l*i. <rrl* toilM #f !*# M< i tl*i 1 W rntoi 1 (llKM< Hftril tintlUii ttr itoMiii ii 1 *1 f vt'k IM 1*1* > Wwt lafNlIt IM ' Ml l tw rr*). Mm laiKIM it..........mill Itotnti iifttta (ftortll aaal m mmi Mi par* literal Mtr **> Ttort ainm riipaaia *1 Itaal hm** trallBH tola* im m. I Hi l|NM TWm wra pra- wImmI lltlaarp riivUl MHrnt. rimul u M iiniiai Ullar u lit (taMt m ttliar. Wvrlill tn t*u) art iaa am* toMl t4 aitor ttotUiJii lialr U i ptoinati All (Ml Mtoittf V* 1mV thM II- H*i*t UO *. tot IM up*) All (Mur wr tiim *h i*r tin >* tatlat (H ita. M>t tip.) t*Ul Ht llm iikiv wm *ii|Mlr J*M*t M am it>iiiulr* Imr thtarnt aartiltir Ur^totaKa 1* It* *wlth toffcii* affaiii imi mu <H. IUh u lillw ap wmillp ipaMaacat HONS 221479 tuu il- (ccariTioauj. amnu K4< (cm '> Mhar, UMMpaa il <1.. I*Ml h*4p M aa* paaan KM I* M|i Ll.ti nw|i Mtirtif him Mtr-m*n p*. %aa.*# lIM-tMt pfh (WMlhT It141 Caaaaaaratlaaa la .Min Uraatar mn I man aa hi* aa Mm (aaaa **.l Pth) aa* Itf.l ppa la traaiat aatl (ma IF.) t*) H !* aaata. M aahan ma. arhara InillH 11 w mitt aaahara llahhala, H il, 1***1 Ccm ^ HNlitMlCrMmli mlltHU' ' (lift* hhImHi HI nAin< ml., hi* kM * alaaalflChtlaa 1M MW- It mtatM. I(--I trihllmim* m!< i(lhl iat.atltat- (M IK* n*.u*)-H / 1 H<kttiaHmlh*tm Mi > MM Ft*. M?l *- taiau aaat< lanl)i 4cm. Impmm4 riimtitiM 4* 4 MfkU ita*tP aaafa IM tthi mhaaa *1.1 pthl faalllaa 11.4 tthl aamtUt *J tth ifcriNi i k** flllUllfli m1mInniim*tititr** 9Bbf MfU HiU hm git tMgUlMft U*lft *1 Kl H vith Uiihp W Mtent il*f1"*ickl** MM Jm* M- mtmim M HMcUtlM MNU Mhhl (1m4 iNk wai* MU 4kr llMf nifirtt mUm VlMM trtflp* 'HN **! ifMU*tMNjMy tllllkfli* MM* Kl |M(f lf#t Im#> NIi il licit* INI Kla if liter Hill MtlkkllMi NmIi Mtiralp UittM hr ict (Ml IImM m ii tltnft t* wrt* MgMaia *r kJN4 iMl| vtifc Wlftf W*Mfi - | IM M pM1* NbriiiilHf %i mik>-Ifitd *Mtni !IM(M< MM* HONS 221480 TABLE 01 PERCENT DISTRIBUTION OF SYMPTOMS OF YUSHO REPORTED BY 1S9 PATIENTS EXAMINED BEFORE OCTOBER 31, 1961. Symptom* Dark brown pigmentation of nails Distinctive hair foilicies Increased sweating at palms Acneiike skin eruptions Red plaques on limbs Itching Pigmentation of skin Swelling of limbs Stiffened soles in feet and palms of hands Pigmented mucous membrane Increased eye discharge Hyperemia of conjunctiva Transient visual disturbance Jaundice Swelling of upper eyelids Feeling of weakness Numbness in limbs Fever Hearing difficulties Spasm of limbs Headache Vomiting Diarrhea Males (N-S9) Females (N- 100) 13.1 64.0 30.6 17.6 20.2 42.7 73.3 20.2 24.7 36.2 11.1 70.1 36.2 11.2 71.9 31.4 32.6 16.9 J1.0 7.9 30.3 23.6 19.1 73.0 36.0 33.0 12.0 16.0 32.0 72.0 41.0 29.0 47.0 13.0 71.0 33.0 ii.O 74.0 32.0 39.0 19.0 19.0 1.0 39.0 21.0 17.0 Source: Kuratsune et al, 1972 -50- RONS 221481 FICURE I HUMBERINC SYSTEM 3-chloroblphinyl 2,2 \ 3,4 *,5-pentmchloroblph.nyl EXAMPLES OF- HOWNCLATURE SYSTEM OF CHLOROBIPHENYL COMPOUNDS NUMBER OF ISOMERS AND PERCENT CHLORINE FOR THE 10 CHLOROBIPHENYL (PCB) CLASSES Chiorobiphenyl Empirical Formula No. of Isomers Weight % Cl mono dl trl tetri pent! hexa hepti OCtl none deci C i,H,Cl C nHtCl 2 C ,,HtC1 3 C uH.Cl 4 C uHfCl 5 C l,HCl 6 C nHiCl 7 C uHiCl S C nHCl 9 c ia io 3 12 24 42 46 42 24 12 3 1 -51- 18.79 31.77 41.30 48.56 54.30 58.93 62.77 65.98 68.73 71.18 NONS 221482 FICURE II CMarliwt* CMw-ImIM Source: Xlabreu|h, 1974 HtrckWlMta* FICURE III CHLORODIBENZOFURAN TYPES AND CONCENTRATIONS IN COMMERCIAL PCS PREPARATIONS Chlorodibenzofurans Mixture* dl trl tetri penta hexa hepta Total (1) 1014 (1) 1014 (1) 1241 (1) 1234 (1) 1234 (1) 1240 (1) 1240 (2) A-40 (3) OP-4 (4) K300 (4) K400 (4) K300 (4) K400 0.3 (c)*** (e) <0.0( 0.3 0.1 0.2 0.1 0.2 1.4 0.7 (a) (e) (a) <0.0001 1.2 0.2 0.4 0.4 0.3 3.0 10.0 (a) (c) (a) (a) <0.0001 0.3 1.4 0.9 0.3 0.3 2.2 2.9 (c) (b) 0.3 2.0 1.7 1.3 1.0 0.1 S.4 13.4 1-1.3 17-11 (a) 2,5-4 (b) 3-5 *(1) Aroclor, (2) Clophen, (3) Phenocior, (4) Kenechior **(), (b), (c)i (d), (e) represent relative amounts in increasing order HONS 221483 riGURE tv Responses of primates and rats to PCB%* Response Susceptibility to toxicity Acne Hyperpigmentation of skin Alopecia Hyperactive Meibomian glands Conjunctivitis Oedema of eyelids Subcutaneous oedema Keratin cysts In hair follicles Hyperplasia of hair follicle epithelium Gastric hyperplasia Thymic atrophy Hepatic hypertrophy Liver enzyme change Decreased no. of red-blood cells Decreased haemoglobin Serum hyperlipidaemla Leucocytes is - Man Monkey Rat High Yes Yes NA Yes Yes Yes Yes Yes Yes NA NA Yes NA Yes Yes Yes Yes High Yes Only infants Yes Yes Yes Yes Yes Yes Yes Yes NA Yes Yes Yes Yes Hypolipidaemia Yes Moderate No No No No No No No No No No Yes Yes Yes No No Yes No Sources IARC, 1971 This table summarizes acute and subacute clinical effects but does not include chronic or delayed effects such as reproductive effects or cancer. -53- ttONS 221484